Cephalotaxus harringtonia, commonly known as the Japanese plum-yew, is a small evergreen shrub native to Eastern Asia. Alcoholic extracts of the powdered leaves and stems of Cephalotaxus genera yielded cephalotaxine as the most abundant alkaloid constituent (L. Huang and Z. Xue, Alkaloids 1984, 23, 157-226; W. W. Paudler, J. McKay and G. I. Kerley, J. Org. Chem. 1963, 28, 2194). While cephalotaxine accounts for approximately 50% of the mass of the crude alkaloid extract mixture, several minor constituents have also been identified. Among these are several rare C3-ester derivatives (K. L. Mikolajczak, C. R. Smith and R. G. Powell, Tetrahedron 1972, 28, 1995; R. G. Powell, D. Weisleder, C. R. Smith, Jr. and W. K. Rohwedder, Tetrahedron Lett. 1970, 815-818; I. Takano, I. Yasuda, M. Nishijima, Y. Hitotsuyanagi, K. Takeya and H. Itokawa, J. Nat. Prod. 1996, 59, 965-967; D. Z. Wang, G. E. Ma and R. S. Xu, Acta pharmaceutica Sinica 1992, 27, 173-177).

The cytotoxic properties of the cephalotaxus esters arise from reversible inhibition of protein synthesis (M. T. Huang, Mol. Pharmacol. 1975, 11, 511-519) via induction of rapid breakdown of the polyribosome, with concomitant release of the polypeptide chain (M. Fresno, A. Jimenez and D. Vazquez, Eur. J. Biochem. 1977, 72, 323-330). The remarkable anti-leukemia activity of several Cephalotaxus esters spawned intense investigations into their therapeutic potential. Several Cephalotaxus esters demonstrate acute toxicity toward various murine leukemia, murine lymphoma, and human epidermoid carcinoma cells (H. Morita, M. Arisaka, N. Yoshida and J. Kobayashi, Tetrahedron 2000, 56, 2929-2934; Powell, et al., supra). Homoharringtonine (HHT) has advanced through clinical studies and is now used for the treatment of chronic myeloid leukemia. However, difficulties in production, hematologic toxicity, and susceptibility to multidrug resistance (MDR) have hindered its clinical development (Z. Benderra, H. Morjani, A. Trussardi and M. Manfait, Leukemia 1998, 12, 1539-1544).
Cephalotaxine itself has been found to be biologically inactive (M. A. J. Miah, T. Hudlicky and J. W. Reed, Alkaloids 1998, 51, 199-269), highlighting the necessity for an elaborate C3 ester side chain for anticancer activity. However, the naturally occurring ester derivatives are typically attainable in only <0.1% of the plant dry weight. While certain cephalotaxus ester derivatives, namely HHT, are available through semisynthetic methods, such approaches are not appropriate for other bioactive members of the family. A versatile and streamlined synthetic approach will allow for the chemical synthesis of virtually any cephalotaxus ester, and will enable cytotoxic profile evaluation of cephalotaxine derivatives in efforts to combat multidrug resistance.